RECURRENT SEVERE HYPERCALCEMIA IN TUBERCULOUS PLEURITIS:SUCCESSFUL STEROID SPARING MANAGEMENT WITH DENOSUMAB IN ADVANCED CHRONIC KIDNEY DISEASE

Hypercalcemia secondary to granulomatous disease is uncommon and often poses diagnostic and therapeutic challenges, especially in patients with chronic kidney disease (CKD). In CKD, reduced renal function leads to significant accumulation of inactive PTH metabolites which poses analytical challenges especially when older generation PTH assays are employed resulting in falsely elevated PTH measurements that may not reflect true parathyroid gland activity 

We describe a diagnostically challenging case of recurrent severe hypercalcemia requiring two hospitalisation stays in a patient with stage 4 CKD and recently diagnosed tuberculous pleuritis. A 69-year-old man with stage 4 CKD of uncertain aetiology, prior rectal cancer resection, and vascular dementia was referred for evaluation of recurrent acute kidney injury (AKI). His AKI episodes had been attributed to obstructive uropathy from benign prostatic hyperplasia. He was noted to have severe hypercalcemia (corrected calcium 3.30 mmol/L) with a suppressed intact parathyroid hormone (iPTH) level of 2.06 pmol/L. The PTH level was low but not fully suppressed given the severe hypercalcemia (reference range: 2.1-2.6mmol/L). Laboratory results showed normal alkaline phosphatase, high-normal phosphate (1.55 mmol/L), and sufficient 25-hydroxyvitamin D levels (44 [WL1] µg/L [reference range 30-100 ug/L]). Serum PTHrP was normal at 1.5 pmol/L (normal <4.2pmol/L). Multiple myeloma panel was negative and imaging (CT thorax-abdomen-pelvis) revealed a loculated right-sided pleural effusion and reticulonodular opacities in the right upper lobe. A pleural biopsy showed granulomatous inflammation, though TB PCR was negative. Given the histological findings and clinical context, a diagnosis of tuberculous pleuritis was made, and standard anti-tuberculous therapy was commenced. Calcium levels initially improved with hydration alone, but he was readmitted a month later with recurrent KDIGO stage 3 AKI and corrected calcium of 3.18 mmol/L. Repeat 25-hydroxyvitamin D was within the reference range. Given the risks of steroid therapy in this frail patient with advanced CKD and diabetes, we opted for subcutaneous calcitonin (250units every 8 hours for a total of three days) followed by for a single 60 mg subcutaneous dose of denosumab following a brief course of intravenous hydration. Prior to denosumab injection, we assessed the risk of adynamic bone disease to be low because of normal levels of alkaline phosphatase (ranging from 64 - 76 U/L). His serum calcium normalized within one week (2.38 mmol/L), accompanied by resolution of AKI. He remained normocalcemic at follow-up.

Common causes of hypercalcemia requiring hospitalisation are  primary hyperparathyroidism and malignancy.Malignancy can cause hypercalcaemia through parathyroid-mediated mechanism (PTH-dependent) or PTH-independent mechanism e.g. bone metastasis. PTH-independent hypercalcemia due to granulomatous disease such as sarcoidosis or tuberculosis are less common

Renal impairment is associated with hypercalcemia in the setting of primary and tertiary hyperparathyroidism. Owing to dysregulation of vitamin D and parathyroid hormone mechanism, the interpretation of PTH and vitamin D levels in patients with CKD stage 4-5 is less clear. Management of severe hypercalcemia in patients with CKD stage 4 (not yet on dialysis) is challenging because of caution needed with aggressive fluid therapy and bisphosphonates which have detrimental effects to fluid status and renal function. Although denosumab is most often used in the setting of malignancy-related hypercalcemia, its role in other causes of hypercalcemia, including granulomatous disease, deserves further exploration. To our knowledge, this is one of the few reported cases of successful denosumab use in TB-associated hypercalcemia

Here we discuss a unique case of patient with tuberculous infection, that required two hospitalisation stays for recurrent severe hypercalcemia. Calcitonin and denosumab combination was used with a safe short-term outcome. Denosumab is an option for the treatment of refractory hypercalcemia in the setting of low creatinine clearance; however, careful monitoring of calcium levels post-therapy is essential after administration especially in those deficient in vitamin D.